Fibrous tissues of the musculoskeletal system are plagued by their poor intrinsic healing capacity. In the previous funding cycle, we developed enabling technologies towards the production of a novel class of composite electrospun scaffolds, and used these scaffolds to develop cell-based tissue engineered constructs with native-like tissue properties and organization. In this competitive renewal, we shift our focus to using these enabling technologies to enhance endogenous tissue repair. Our focus is on the knee meniscus, a fibrous tissue critical for proper load transfer and for which current repair strategies do not restore function. The overall objective of this renewal is to use these scaffolds to deliver multiple agents over different temporal scales to specifically address the inherent limitations to endogenous meniscus repair. These limitations in the adult include synovial inflammation, low endogenous cellularity, and hindered cell mobility to the wound interface. This proposal will employ composite scaffolds (developed during the first funding cycle) that provide a stable fiber fraction (polycaprolactone (PCL), to provide an instructional pattern and mechanical stability), a sacrificial fiber fraction (polyethylene oxide (PEO), to define initial scaffold porosity), and an MMP-cleavable hyaluronic acid (HA) fiber fraction (that degrades in response to elevated proteolytic activity in synovial fluid of patients with meniscus damage). Degradation of the HA fiber fraction will both enhance cellular infiltration (by increasing scaffol porosity) and at the same time reduce degradation of nascent repair tissue (via competitive inhibition of synovial MMPs). These composite scaffolds will also address limited cellular mobility through the dense surrounding ECM by rapidly and locally decreasing nuclear stiffness (via the delivery of agents that reduce heterochromatin content and/or Lamin A/C processing) in endogenous meniscus cells. Finally, these scaffolds will selectively recruit endogenous meniscus cells towards the wound interface, to accelerate and sustain the repair process, via the delivery of stromal derived factor-1? (SDF-1?), a potent cytokine that increases meniscal cell migration. The synergistic interactions of these different repair adjuvants will be validated through in vitro scaffold and meniscal explant studies, and then tested in our large animal (ovine) meniscus defect model. If successful, these studies and technologies will set the stage for clinical translation and treatment of human meniscal injury by overcoming the inherent limitations to endogenous meniscus repair.